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Trial registered on ANZCTR


Registration number
ACTRN12616000401459p
Ethics application status
Not yet submitted
Date submitted
7/03/2016
Date registered
29/03/2016
Date last updated
11/10/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
Probiotics and Orotic Acid for treatment resistant depression
Scientific title
Project title: A randomised placebo controlled clinical trial investigating the role of orotate and probiotics co-administered with antidepressant medications for the management of treatment resistant depression.
Secondary ID [1] 288704 0
NIL
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Treatment resistant depression with high risk of relapse 297926 0
Mental Health 297927 0
Condition category
Condition code
Mental Health 298088 298088 0 0
Depression
Alternative and Complementary Medicine 298089 298089 0 0
Other alternative and complementary medicine

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The project intervention will consist of n=250 using a randomised parallel treatment trial to test the efficacy of the oral administration of specific strain probiotics and orotic acid administered in conjunction with selective serotonin uptake inhibiters (SSRI) for treatment resistant depression.
The project time line will consist of rolling recruitment and block allocation to conditions. All participants will be inducted into a 2 week precondition where they will receive 2x placebo capsules daily to identify placebo responders. Placebo capsules (microcellulose) will be identical the probiotic and the Mg orotate tablets used in the experimental phase of the study. All participants are then allocated to a 2 week probiotic run in period and receive 2 probiotic capsules daily followed by random allocation to either 1. probiotic + orotic acid (Magnesium form: Mg orotate) and 2., probiotic and placebo groups for 8 weeks with a 4 week follow up assessment. Total study duration is 16 weeks for participants with repeated recruitments over a minimum of 24 months. .
Probiotic: A daily dose of 2 probiotic capsules taken orally, 1 x morning and 1 x evening with a meal. Each capsule contains 50 billion colony-forming units (CFU) of live organisms (Lactobacillus acidophilus +Lactobacillus casei +Lactobacillus rhamnosus JB-1.)
Orotic acid: A daily oral dose of 4 x Mg orotate taken 2 x morning and 2 x evening with a meal, yielding 1600mg of orotate.
Each participant will be taking SSRI medication prescribed by their own medical practitioner as part of the selection criteria, and they will continue taking their medication throughout the study.
Supplement and SSRI compliance will be monitored by fortnightly contact with each participant by a research assistant and a dosage log book that must be completed by participants on a daily basis throughout the study.
Intervention code [1] 294130 0
Treatment: Other
Comparator / control treatment
The control is conducted in 2 phases, firstly the placebo responder screening (2 weeks).
The experimental control consists of administering a placebo in place of Mg orotate in parallel group 2, while continuing to take the probiotic.
Control group
Placebo

Outcomes
Primary outcome [1] 297604 0
Beck Depression Inventory Score will provide primary symptom response data. Outcome 1 consists of evaluating BDI during and after treatment.
Timepoint [1] 297604 0
BDI scores will be administered at study intake, end of placebo screen condition, end of 2 week run in phase, and end point of experimental phase at 8 weeks and at 4 week follow up.
Primary outcome [2] 297606 0
Dysbiosis is assessed using fecal sequencing and analysis from samples provided by each participant.
Timepoint [2] 297606 0
Fecal sequence at intake week -1 and study endpoint, week 8 and follow up week 4.
Primary outcome [3] 297607 0
Lipopolysacharide levels (LPS) will be assessed using blood tests provided by individual participants as a marker of systemic inflammation.
Timepoint [3] 297607 0
LPS blood samples drawn at week 1, 8 and follow up, week 4,
Secondary outcome [1] 321575 0
The outcome questionnaire (OQ45) will be administered to assesses functional symptom and distress.
Timepoint [1] 321575 0
Intake, placebo screen at -2 weeks, weekly during run in probiotic phase 2 weeks, weekly during experimental phase 8 weeks, and at a single point follow up, 4 weeks.
Secondary outcome [2] 322056 0
Blood cytokine levels as an inflammation marker
Timepoint [2] 322056 0
Samples provided at experimental phase allocation, endpoint 8 weeks and follow up 4weeks.

Eligibility
Key inclusion criteria
1. Be depressed,, with depression as primary diagnosis, while taking SSRI antidepressant medication as prescribed by a doctor
2. Currently be under the management of a medical practitioner e.g. family doctor or a psychiatrist
3. Have a history of depression that has not responded well to medication, with at least 2 previous episodes
4. Be over 18 years of age and have the capacity to provide informed consent
5. Have the willingness and ability to comply with assessment protocols of the study







Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Resistant depression not being the primary diagnosis
2. Current substance misuse
3. Other psychiatric disorder as primary diagnosis
4. Active suicidality
5. Not able to understand or conform to study requirements
6. Subject to a mental health or guardianship order

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Participants will be randomly allocated to conditions. Randomisation will be conducted by a person not involved with the selection and assessment of participants.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Permuted randomisation carried out by a research assistant who was not involved with selection or assessment of participants, to 1 = probiotic + mg orotate and SSRI or 2 = probiotic + placebo and SSRI. Rolling allocation will occur during recruitment until n=250.

Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
2 x pre experimental conditions, being placebo screen x 2 weeks, and probiotic run in phase x 2 weeks, then experimental conditions begin.
Phase
Not Applicable
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Power calculations were based on effect sizes achieved from our pilot data using adjuvant treatments. We assume the standard deviation of the difference in responses between treatments for the same patient is 21 units, and that alpha=0.05. To identify a clinically important between-treatment difference of 5 units or greater, with 80% power, we need to obtain complete outcome data on 140 individual patients. Assuming a notional 30% of participants who enrol for the study do not complete all intervals of measurement, as a sample validity measure, the recruitment target will be expanded to n=200 participants for this study. Further, it is possible that 20% of the sample will be placebo responders in the screen condition, therefore an additional n=50 participants will be recruited resulting in a total of n=250 participants.

Data will be analysed using SPSS statistical software package version 17.0. For the BDI, QOL, OQ45 scores repeated measures analyses of variance [ANOVA] will be conducted to investigate the relationship between matched differences between the 2 treatments on pre-post- and follow up and weekly symptom change scores. T-tests will be conducted for significant and marginally significant within group effects. Regression tests will be employed to examine measures of association between variables. Non-parametric tests will be employed if data is skewed from normality. Biological test data will be reported in full and entered as either scored variables or categorical data for the different analyses.

Recruitment
Recruitment status
Withdrawn
Reason for early stopping/withdrawal
Lack of funding/staff/facilities
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD

Funding & Sponsors
Funding source category [1] 293064 0
Self funded/Unfunded
Name [1] 293064 0
Address [1] 293064 0
Country [1] 293064 0
Primary sponsor type
Individual
Name
Professor Luis Vitetta
Address
Sydney Medical School
Edward Ford Building A27
The University of Sydney
NSW 2006
AUSTRALIA
Country
Australia
Secondary sponsor category [1] 291845 0
None
Name [1] 291845 0
None
Address [1] 291845 0
None
Country [1] 291845 0

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 294573 0
Medical Research Ethics Committee (MREC)
Ethics committee address [1] 294573 0
UQ Research & Innovation
Cumbrae-Stewart Building (72)
THE UNIVERSITY OF QUEENSLAND QLD 4072
Ethics committee country [1] 294573 0
Australia
Date submitted for ethics approval [1] 294573 0
02/09/2016
Approval date [1] 294573 0
Ethics approval number [1] 294573 0

Summary
Brief summary
The aim of this research is to evaluate the role of dysbiosis and probiotics and orotic acid as a treatment for depressive illness that does not respond to standard medication treatment.
The mechanisms of probiotics in the treatment of dysbiosis and systemic inflammation and orotic acid as a treatment for resistant depression will also be evaluated. Significance: Developing effective and safe treatments for resistant depression is essential as this group presents a significant burden of care to the health system and generally have poorer vocational and quality of life outcomes and are at increased risk of morbidity and mortality. Dysbiosis and ensuing systemic inflammation has been strongly implicated in depression that has a poor treatment response. Orotic acid rapidly metabolises into uridine which has proven antidepressant effects through mechanisms different to antidepressant medication. Orotic acid demonstrated efficacy in our previous pilot work. The expected outcome of this study is to provide preliminary efficacy and safety data, and elucidate the mechanism of probiotics and orotoic acid as an adjuvant therapy with one class of standard medication.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 64202 0
Prof Luis Vitetta
Address 64202 0
Sydney Medical School
Edward Ford Building A27
The University of Sydney
NSW 2006
AUSTRALIA
Country 64202 0
Australia
Phone 64202 0
+61 402263316
Fax 64202 0
Email 64202 0
luis.vitetta@sydney.edu.au
Contact person for public queries
Name 64203 0
Dr Matthew Bambling
Address 64203 0
School of Medicine
Mayne Medical School
288 Herston Road
Herston QLD 4006
Australia
Country 64203 0
Australia
Phone 64203 0
+61 466532314
Fax 64203 0
Email 64203 0
m.bambling@uq.edu.au
Contact person for scientific queries
Name 64204 0
Dr Matthew Bambling
Address 64204 0
School of Medicine
Mayne Medical School
288 Herston Road
Herston QLD 4006
Australia
Country 64204 0
Australia
Phone 64204 0
+61 466532314
Fax 64204 0
Email 64204 0
m.bambling@uq.edu.au

No information has been provided regarding IPD availability
Summary results
No Results